Background Annexin A1 (AnxA1) is an important endogenous glucocoticoid protein that contributes to the suppression of inflammation by limiting the production of neutrophil and pro-inflammatory cytokines. This study aims to determine the clinical predictivity value of blood AnxA1 levels in patients with mild and severe-critical pneumonia induced by COVID-19. Methods This study employed a prospective, case-control study design and was conducted at Ankara Training and Research hospital between 10 February 2021 and 15 March 2021. A total of 74 patients (42 of whom had moderate and 32 of whom had severe/critical cases of COVID-19 disease according to World Health Organization guidelines) and 50 nonsymptomatic healthy volunteers participated in the study. Blood samples were taken from patients at the time of hospital admission, after which serum was isolated. Following the isolation of serum, AnxA1 levels were evaluated using the enzyme-linked immunosorbent assay method. Results The serum AnxA1 levels were measured as 25.5 (18.6-38.6) ng/ml in the control group, 21.2 (14.7-32) ng/ml in the moderate disease group, and 14.8 (9.7-26.8) ng/ml in the severe/critical disease group. Serum AnxA1 levels were significantly lower in the severe/critical disease group compared with the control and moderate disease groups (P = .01 and P = .0001, respectively). Using receiver operating characteristic analysis, a larger area under the curve (AUC) for the serum AnxA1 levels of the control group (AUC = 0.715, 95% CI = 0.626-0.803; P = .0001) was calculated compared with the COVID-19 patient group for the diagnosis of COVID-19 disease. The AnxA1 level was found to be 80% sensitive and 54.1% specific at a cut-off level of 18.5 ng/ml for the diagnosis of COVID-19 disease. Moreover, the AnxA1 level was found to be 69.8% sensitive and 58.1% specific at a cut-off level of 17.2 ng/ml in predicting the need for intensive care unit (ICU) treatment. Conclusion AnxA1 levels may be a beneficial biomarker in the diagnosis of COVID-19 pneumonia and in predicting the need for ICU treatment in patients with COVID-19 pneumonia at the time of admission to the emergency department.